Oxidase-negative Fibers Research Articles

Polymyositis with cytochrome C oxidase negative fibers—a pathological and clinical challenge

Polymyositis (PM) with cytochrome C oxidase negative fibers also referred to as PM with mitochondrial pathology (PM-Mito) is characterized by the symptoms of inclusion body myositis (IBM) and by the myopathological findings of PM except for an increase of muscle fibers with insufficient mitochondrial cytochrome C oxidase activity. Few PM-Mito cases are published; mitochondrial ultrastructure has not been studied in these patients. We report 2 PM-Mito patients with later onset than usually seen in IBM and poor responsiveness to glucocorticoids. Electron microscopy of muscle fibers showed irregular mitochondrial ultrastructure. Sjögren syndrome related antinuclear antibodies (Anti-Ro and Anti-La) were found in one of the two patients but the typical clinical symptoms of Sjögren syndrome such as xerostomia and keratoconjunctivitis were absent in this patient. Taken together, our observations, viewed in conjunction with the current literature, suggest that PM-Mito is an underdiagnosed disease with a multifactorial pathogenesis that should be elucidated in further studies. We want to encourage clinicians and pathologists to consider the possibility of PM-Mito in patients with atypical PM or sIBM.

Mitochondrial DNA depletion syndrome presenting with ataxia and external ophthalmoplegia: Case report

The mitochondrial DNA depletion syndromes are autosomal recessive disorders characterized by decreased mitochondrial DNA copy number in affected tissues. Mutations in 2 genes involved in deoxyribonucleotide metabolism, the deoxyguanosine kinase gene and the thymidine kinase 2 gene, had been related to this syndrome. This study aims to describe the clinical, histochemical, biochemical and molecular diagnosis of one Egyptian pediatric patient with the myopathic form of mitochondrial depletion syndrome. The patient presented to Cairo University Pediatric Hospital with the clinical suspicion of mitochondrial encephalomyopathy. Histochemical and biochemical studies of the respiratory chain complexes were performed on the muscle biopsy specimen from the patient. Molecular diagnosis was done by quantitative radioactive Southern blot and sequencing analysis of the whole coding regions of the TK2 gene. Histochemical staining revealed cytochrome oxidase negative fibers and increased staining for succinate dehydrogenase. The activity of complex I was not detected and complex IV activity was about 46% of age matched controls. Southern blot analysis showed reduction of the mitochondrial/nuclear DNA ratio, the degree of depletion was around 30% of aged-matched controls. Sequencing analysis of the TK2 gene revealed no sequence variation. Targeted molecular diagnosis based on the biochemical analysis of the respiratory chain enzymes makes the molecular evaluation of mitochondrial disorders much easier. Involvement of other nuclear genes rather than TK2 gene in the pathogenesis of the myopathic form of mitochondrial depletion syndrome should be considered.

MELAS-like encephalomyopathy caused by a new pathogenic mutation in the mitochondrial DNA encoded cytochrome c oxidase subunit I

We report a 35-year-old woman presenting a stroke-like episode with transitory aphasia followed by generalized tonic-clonic seizures. She had severe hearing loss and suffered from frequent episodes of migraine. Although a brain MRI disclosed a T2-hyperintense lesion in the left parietal lobe, she had hardly any long-term sequela. Exercise intolerance, myalgias and limb-girdle muscle weakness indicated a slowly progressive myopathy. Extra-neurological features included short stature, and secondary amenorrhea with low gonadotropin levels, indicating secondary hypogonadism. However, she had three mutation-free, healthy children by ovarian stimulation. A muscle biopsy showed ragged-red, cytochrome c oxidase-negative fibers, and an isolated defect of cytochrome c oxidase activity in muscle mitochondria. Sequence analysis of muscle mtDNA revealed a previously unreported heteroplasmic m.6597C>A transversion in the MTCOI gene, encoding subunit I of cytochrome c oxidase, corresponding to p.Q232K aminoacid change. Analysis on transmitochondrial cybrids demonstrated that the mutation is indeed associated with COX deficiency, i.e. pathogenic.

PEO1 Gene (Twinkle) Mutation and Multi-Organ Failure Following Propofol Infusion (IN7-1.005)

Objective: Present a case of mitochondrial myopathy and multi-organ failure following propofol infusion. Background Mitochondrial DNA deletions are associated with a variety of clinical syndromes including chronic progressive external ophthalmoplegia (CPEO) due to nuclear as opposed to mitochondrial mutations. The nuclear PEO1 gene encodes for Twinkle, a helicase required for mitochondrial DNA replication and stability. Clinically, autosomal dominant Twinkle mutations are associated with CPEO. POLG mutations result in defects in the DNA polymerase gamma and can be associated with either autosomal dominant or autosomal recessive CPEO. Mitochondrial myopathies are associated with a sensitivity to propofol, and patients are more susceptible to developing a propofol infusion syndrome with resultant multi-organ dysfunction. Design/Methods: Literature review and illustrative case. Results: A 62-year old woman with a history of congenital ptosis and ophthalmoplegia was admitted for elective right eye enucleation for a corneal ulcer following levator resection. During the procedure, she was given propofol for anesthesia and the surgery was uneventful. Postoperatively, she developed a series of medical complications including Takotsubo cardiomyopathy, congestive heart failure, acute renal failure, and encephalopathy. She also developed dysarthria, bifacial and proximal muscle weakness, and difficulty weaning from the ventilator. Muscle biopsy was done showing a mitochondrial myopathy with scattered ragged red fibers and cytochrome oxidase negative muscle fibers. Genetic analysis showed nuclear mutations in the PEO1 and POLG genes. Conclusions: This patient had a mitochondrial myopathy presenting with CPEO, and after elective surgery, developed muti-organ dysfunction. She had the PEO1 mutation in addition to a POLG mutation. The literature on propofol use in mitochondrial myopathies is limited, but it has been associated with propofol infusion syndrome, and may have led to her poor clinical course. Disclosure: Dr. Harrison has nothing to disclose. Dr. Valerio has nothing to disclose. Dr. Buffam has nothing to disclose. Dr. Mezei has received personal compensation for activities with Genzyme as a speaker.

Subacute progressive ophthalmoplegia associated with dermatomyositis

Dermatomyositis is a systemic autoimmune disorder that primarily affects the skin and skeletal muscle in the extremities, and is characterized by weakness of the proximal groups of limb muscles. Extraocular muscle involvement is a very rare manifestation of dermatomyositis [5, 8]. We herein report a patient who manifested dermatomyositis with subacute progressive ophthalmoplegia. The patient was a 53-year-old Japanese male who presented with myalgia and difficulty in climbing stairs. He developed progressive diplopia with eyelid edema and ocular pain 2 weeks after presentation, followed by difficulties in raising his arms. No autoimmune, endocrinopathy, or malignant diseases were observed. The physical examination revealed the presence of Gottron’s papules on the dorsal surface of the hands, and a neurological examination showed symmetrical weakness of the proximal muscles, including the upper limbs muscles, and bilateral ophthalmoplegia with total limitations of eye movements (Fig. 1). There was no weakness of the facial muscles or bulbar palsy. Laboratory tests revealed an increased creatine kinase (CK) level (10,808 U/l; normal range, 25–190). There was no abnormal thyroid function or serum autoantibody, including antinuclear antibody, anti-acetylcholine receptor antibody, and anti-thyroid antibodies. No malignant tumors, including thymoma or thymic hyperplasia, were observed using whole-body CT and PET imaging. Intravenous edrophonium had no effect on the ophthalmoplegia. The repetitive nerve stimulation test was normal. The muscle biopsy at the left vastus medialis muscle revealed inflammatory myopathic changes, which showed the invasion of mononuclear cells into the interfascicular septae and within the fascicles, perifascicular atrophy, and variations in the muscle fiber size. An immunohistochemical analysis showed the mononuclear cells to be CD4and CD8-positive lymphocytes. Ragged red fiber or cytochrome c oxidase-negative fibers were absent. The patient was treated with 60 mg/day oral prednisolone. His ocular impairment, weakness of the proximal muscles, and elevated CK values became markedly improved 1 month after the steroid therapy. Orbital magnetic resonance imaging (MRI) scans revealed an increased thickness of the extraocular muscles on T1-weighted images (Fig. 2a) and high-intensity signals of the extraocular muscles on fat-suppressed T2-weighted images (Fig. 2c), which were both improved after the steroid therapy (Fig. 2b, d). No myositis-associated autoantibodies, including anti Jo-1, PM-Scl-100, PL-7, PL-12, EJ, OJ, KS, M2, Ku (p70/80), SRP, Rib-P antibodies and the antimitochondrial antibody of M2 subtype, were detectable in the serum. Previous reports have suggested that the ophthalmoplegia observed in inflammatory myopathies is caused by the S. Kono (&) T. Bunai T. Konishi K. Shirakawa H. Miyajima First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu 431-3192, Japan e-mail: satokono@hama-med.ac.jp

Orbicularis oculi: morphological changes mimicking mitochondrial cytopathy in a series of control normal muscles

Orbicularis oculi (OO) muscle has recently proposed as a suitable muscle for biopsy to diagnose mitochondrial cyopathy: Enzyme histochemical and immunohistochemical studies were performed on OO muscle obtained from 18 patients aged 37-87 years (median 64 years), 6 males, 12 females, who were undergoing routine upper blepharoplasty surgery. We confirmed the marked type II fibre (fast myosin heavy chain) predominance (89%) but also noted a different proportion and distribution of mitochondria in these fibres with occasional pseudo-'ragged-red' fibres with prominent subsarcolemmal and cytoplasmic aggregation of mitochondria. Cytochrome oxidase-negative fibres and true 'ragged-red' fibres were found at all ages over 40 years at levels that approach those used for diagnosis of mitochondrial cytopathy in peripheral or limb skeletal muscles. We would therefore urge caution in the use of OO as muscle biopsy for diagnosis of mitochondrial cytopathy and advise concomitant biopsy of limb skeletal muscle and/or supplementary genetic studies.

The novel mitochondrial tRNAAsn gene mutation m.5709T>C produces ophthalmoparesis and respiratory impairment

Although mutations in mitochondrial tRNAs constitute the most common mtDNA defect, the presence of pathological variants in mitochondrial tRNA(Asn) is extremely rare. We were able to identify a novel mtDNA tRNA(Asn) gene pathogenic mutation associated with a myopathic phenotype and a previously unreported respiratory impairment. Our proband is an adult woman with ophthalmoparesis and respiratory impairment. Her muscle biopsy presented several cytochrome c oxidase-negative (COX-) fibres and signs of mitochondrial proliferation (ragged red fibres). Sequence analysis of the muscle-derived mtDNA revealed an m.5709T>C substitution, affecting mitochondrial tRNA(Asn) gene. Restriction-fragment length polymorphism analysis of the mutation in isolated muscle fibres showed that a threshold of at least 91.9% mutated mtDNA results in the COX deficiency phenotype. The new phenotype further increases the clinical spectrum of mitochondrial diseases caused by mutations in the tRNA(Asn) gene.

Novel POLG Splice Site Mutation and Optic Atrophy

To investigate the molecular etiology of 2 unrelated patients with a multisystem mitochondrial disorder accompanied by optic atrophy in one of them. Clinical examination and neurophysiological, radiological, morphological, and molecular analyses. Tertiary care neuromuscular clinic and molecular genetics laboratory. A 65-year-old man (patient 1) with dyschromatopsia and vision loss since childhood developed progressive external ophthalmoplegia, ptosis, and myopathy in the seventh decade of life and was found to have optic atrophy. A 63-year-old man (patient 2) with a similar phenotype, without visual symptoms, experienced also hearing loss and parkinsonism. Description of the clinical and molecular findings. A muscle biopsy specimen showed ragged-red, ragged-blue, and cytochrome c oxidase-negative fibers in both patients. Because optic atrophy in patient 1 suggested an autosomal dominant OPA1-related disorder, the OPA1 gene was first sequenced, the results of which did not detect any mutations. Southern blot and polymerase chain reaction analyses of muscle mitochondrial DNA revealed multiple deletions. Sequencing of POLG detected a novel variant, c.3104 + 3A>T, in both patients. Patient 1 was compound heterozygous for a known p.F749S mutation; patient 2 had p.G848S as the second mutation. Analysis of POLG complementary DNA showed that c.3104 + 3A>T results in skipping of exon 18. Early-onset dyschromatopsia and optic atrophy can occur not only in OPA1-related but also in POLG-related disorders with significant impact on genetic counseling.

A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNAPhe gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease.

POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype

BackgroundThe c.2447G>A (p.R722H) mutation in the gene POLG1 of the catalytic subunit of human mitochondrial polymerase gamma has been previously found in a few occasions but its pathogenicity has remained uncertain. We set out to ascertain its contribution to neuromuscular disease.MethodsProbands from two families with probable mitochondrial disease were examined clinically, muscle and buccal epithelial DNA were analyzed for mtDNA deletions, and the POLG1, POLG2, ANT1 and Twinkle genes were sequenced.ResultsAn adult proband presented with progressive external ophthalmoplegia, sensorineural hearing impairment, diabetes mellitus, dysphagia, a limb myopathy and dementia. Brain MRI showed central and cortical atrophy, and 18F-deoxyglucose PET revealed reduced glucose uptake. Histochemical analysis of muscle disclosed ragged red fibers and cytochrome c oxidase-negative fibers. Electron microscopy showed subsarcolemmal aggregates of morphologically normal mitochondria. Multiple mtDNA deletions were found in the muscle, and sequencing of the POLG1 gene revealed a homozygous c.2447G>A (p.R722H) mutation. His two siblings were also homozygous with respect to the p.R722H mutation and presented with dementia and sensorineural hearing impairment. In another family the p.R722H mutation was found as compound heterozygosity with the common p.W748S mutation in two siblings with mental retardation, ptosis, epilepsy and psychiatric symptoms. The estimated carrier frequency of the p.R722H mutation was 1:135 in the Finnish population. No mutations in POLG2, ANT1 and Twinkle genes were found. Analysis of the POLG1 sequence by homology modeling supported the notion that the p.R722H mutation is pathogenic.ConclusionsThe recessive c.2447G>A (p.R722H) mutation in the linker region of the POLG1 gene is pathogenic for multiple mtDNA deletions in muscle and is associated with a late-onset neurological phenotype as a homozygous state. The onset of the disease can be earlier in compound heterozygotes.

A Novel Heteroplasmic tRNASer(UCN) mtDNA Point Mutation Associated With Progressive Ophthalmoplegia and Dysphagia

We report a novel heteroplasmic mitochondrial DNA mutation in the tRNA gene at nucleotide 7458 (m.7458G>A) in a 26-year-old patient affected with sporadic progressive external ophthalmoplegia associated with dysphagia. Muscle biopsy showed a strong succinate dehydrogenase staining, ragged red fibers, and 15% of cytochrome c oxidase-negative fibers. Activities of mitochondrial respiratory chain complexes I+III and IV were reduced. The mutation was heteroplasmic (75%) in the muscle, but undetectable in accessible tissues from the patient and his maternal relatives. This report expands the molecular heterogeneity of progressive external ophthalmoplegia.

The m.12316G>A mutation in the mitochondrial tRNA Leu(CUN) gene is associated with mitochondrial myopathy and respiratory impairment

Mitochondrial disorders are often associated with mutations in mitochondrial tRNA. Independent observation of the same molecular defect in unrelated subjects is a generally required proof of pathogenicity. A sporadic case of chronic external ophthalmoplegia (cPEO) with ragged red fibres (RRFs) has been previously related to an m.12316G>A substitution in tRNA Leu(CUN). Sequencing muscle-derived mtDNA, we found the m.12316G>A substitution in an adult woman with mitochondrial myopathy and respiratory impairment. Her muscle biopsy presented several cytochrome c oxidase-negative (COX−) fibres, and RRFs as signs of mitochondrial proliferation. Restriction-fragment length polymorphism (RFLP) analysis of the mutation in isolated muscle fibres showed a threshold of at least 60% of mutated mtDNA to determine a COX deficiency phenotype. This second report of the m.12316G>A mutation in a sporadic patient consolidates its pathogenic nature and provides further elements for genetic counselling.

Ketogenic diet slows down mitochondrial myopathy progression in mice

Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies.

Clinical phenotype of autosomal dominant progressive external ophthalmoplegia in a family with a novel mutation in the C10orf2 gene

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder caused by mutations in nuclear genes. Here we report the clinical and genetic features of adPEO in a Chinese family. All patients had gradual onset of ptosis, with or without ophthalmoplegia, around age 30. Thirteen patients had limb weakness around age 40. Eight patients developed dysphagia around age 50. Four patients died of cardiac abnormalities around age 60. Muscle biopsy of the proband indicated mitochondrial myopathy characterized by ragged-red fibers, cytochrome c oxidase-negative fibers, and multiple deletions of mitochondrial DNA. A heterozygous missense mutation of c.1342A>G in the C10orf2 gene resulting in the p.448N>D mutation in the protein was found in the proband and four other affected family members. In summary, we identified an adPEO family with a novel C10orf2 gene mutation that manifested an age-dependent phenotype. It suggests that greater attention must be paid to cardiac abnormalities in the late stages of this disease.

Association of the MELAS m.3243A>G mutation with myositis and the superiority of urine over muscle, blood and hair for mutation detection

A patient with a known family history of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) due to the MT-TL1 m.3243A>G mutation presented with mild myalgia and very minor upper limb proximal muscle weakness. Muscle histology revealed low levels of cytochrome oxidase-negative fibres and non-specific myositis. Using the last “hot cycle” polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), the MELAS MT-TL1 m.3243A>G mutation was only detected in urine, and not in hair, blood or skeletal muscle. This report highlights the need to screen various tissues to achieve an accurate mitochondrial genetic diagnosis and suggests the likelihood of myositis arising secondary to the MELAS MT-TL1 m.3243A>G mutation.

Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

BackgroundIn muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized.MethodsCOX activity staining of liver for light and electron microscopy, muscle stains, blue native gel electrophoresis and activity assays of respiratory chain proteins, their immunolocalisation, mitochondrial and nuclear DNA analysis.ResultsThree unrelated infants showed a mitochondrial mosaic in the liver after staining for COX activity, i.e. hepatocytes with strongly reactive mitochondria were found adjacent to cells with many negative, or barely reactive, mitochondria. Deficiency was most severe in the patient diagnosed with Pearson syndrome. Ragged-red fibers were absent in muscle biopsies of all patients. Enzyme biochemistry was not diagnostic in muscle, fibroblasts and lymphocytes. Blue native gel electrophoresis of liver tissue, but not of muscle, demonstrated a decreased activity of complex IV; in both muscle and liver subcomplexes of complex V were seen. Immunocytochemistry of complex IV confirmed the mosaic pattern in two livers, but not in fibroblasts. MRI of the brain revealed severe white matter cavitation in the Pearson case, but only slight cortical atrophy in the Alpers-Huttenlocher patient, and a normal image in the 3rd. MtDNA in leucocytes showed a common deletion in 50% of the mtDNA molecules of the Pearson patient. In the patient diagnosed with Alpers-Huttenlocher syndrome, mtDNA was depleted for 60% in muscle. In the 3rd patient muscular and hepatic mtDNA was depleted for more than 70%. Mutations in the nuclear encoded gene of POLG were subsequently found in both the 2nd and 3rd patients.ConclusionHistoenzymatic COX staining of a liver biopsy is fast and yields crucial data about the pathogenesis; it indicates whether mtDNA should be assayed. Each time a mitochondrial disorder is suspected and muscle data are non-diagnostic, a liver biopsy should be recommended. Mosaics are probably more frequent than observed until now. A novel pathogenic mutation in POLG is reported.Tentative explanations for the mitochondrial mosaics are, in one patient, unequal partition of mutated mitochondria during mitoses, and in two others, an interaction between products of several genes required for mtDNA maintenance.

Long‐term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA†

Clevudine (Revovir), a pyrimidine nucleoside analogue, is a recently introduced antiviral drug. Clinical trials have demonstrated potent, sustained antiviral activity against hepatitis B virus without specific adverse events. The lack of cytotoxicity and absence of an effect on mitochondrial function have been considered the reasons for the fewer adverse events. However, it came to our attention that several hepatitis B patients developed myopathy during clevudine therapy. Our study was aimed to analyze the clinical and pathological features of patients with clevudine-induced myopathy with some consideration of its pathogenetic mechanism. Seven hepatitis B patients who developed severe skeletal myopathy during clevudine therapy were examined in this study. The demographic data, clinical features, pathological findings, and molecular studies of these patients were analyzed with speculation about the underlying pathogenic mechanisms. All seven patients were treated with clevudine for more than 8 months (8-13 months). In all, the main symptom was slowly progressive proximal muscular weakness over several months. A markedly elevated creatine kinase level and myopathic patterns on electromyography were found. Muscle biopsies revealed severe myonecrosis associated with numerous ragged red fibers, cytochrome c oxidase-negative fibers, and predominant type II fiber atrophy. Molecular studies using quantitative polymerase chain reaction showed a depletion of the mitochondrial DNA in the patients' skeletal muscle. To the best of our knowledge, this is the first report of myopathy associated with clevudine therapy. This study has clearly shown that long-term clevudine therapy can induce the depletion of mitochondrial DNA and lead to mitochondrial myopathy associated with myonecrosis. Careful clinical and laboratory attention should be paid to patients on long-term clevudine therapy for this skeletal muscle dysfunction.

Inflammatory myopathies with mitochondrial pathology and protein aggregates

Objectives To compare the clinical course and muscle biopsy features of polymyositis with mitochondrial pathology (PM-Mito) to inclusion body myositis (IBM) and steroid-responsive inflammatory myopathies (polymyositis). Methods We compared clinical, laboratory and myopathologic features in a retrospective study of patients with PM-Mito (23), IBM (26) and polymyositis (12). Results Selective weakness in the quadriceps or finger flexors was common in PM-Mito (62%) and IBM (87%). Weakness progressed more slowly in PM-Mito than in IBM. PM-Mito patients with more rapidly progressive weakness had more cytochrome oxidase negative muscle fibers. There was no history of benefit from corticosteroid treatment in any PM-Mito or IBM patients. B-cell foci were absent in IBM and PM-Mito. LC3, an autophagy marker, and αB-crystallin were common in aggregates in PM-Mito and IBM, but not polymyositis. SMI-31 and TDP-43 positive aggregates were common in IBM but not in PM-Mito or polymyositis. β-amyloid showed no differences in aggregates among the three groups. Conclusions PM-Mito and IBM may be part of the same disease spectrum. PM-Mito has more slowly progressive weakness than IBM and rarely has TDP-43 or SMI-31 staining aggregates in muscle fibers. The most frequent proteins in aggregates in both PM-Mito and IBM are LC3, an autophagy marker, and αB-crystallin. Alterations in autophagic degradation pathways may be a common pathogenic mechanism in PM-Mito and IBM. In pathologically typical polymyositis, staining for mitochondrial enzyme activity, aggregates and B-cells helps to distinguish PM-Mito from inflammatory myopathy syndromes that are more likely to respond to corticosteroid treatment.

Unusual presentations of patients with the mitochondrial MERRF mutation A8344G

MERRF is typically characterized by myoclonus, generalized seizures and ragged-red fibers in muscular biopsy. We report a family (harbouring the A8344G mutation) with a late onset of the disease and an uncommon clinical manifestation, including episodes of reversible respiratory failure, the presence of ophthalmoplegia, and the absence of seizures and myoclonus in most subjects. We conducted histochemical, biochemical and molecular genetic studies. Mutation analysis revealed that the level of mutated mitochondrial DNA (mtDNA) was above 80% in the skeletal muscle of all siblings. Nevertheless, one severely affected individual did neither present cytochrome c oxidase-negative fibers nor ragged-red fibers in the skeletal muscle biopsy. These data extend the phenotypic range associated with the MERRF syndrome. We suggest that the analysis of mtDNA could be of importance in many cases of unclear multisystem disorders in later life.

Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations

Mutations in POLG gene are responsible for a wide spectrum of clinical disorders with altered mitochondrial DNA (mtDNA) integrity, including mtDNA multiple deletions and depletion. Sensory ataxic neuropathy with ophthalmoparesis (SANDO) caused by mutations in POLG gene, fulfilling the clinical triad of sensory ataxic neuropathy, dysarthria and/or dysphagia and ophthalmoparesis, has described in a few reports. Here we described five cases of adult onset autosomal recessive sensory ataxic neuropathy with ophthalmoplegia. All patients had ataxia, neuropathy, myopathy, and progressive external ophthalmoplegia (PEO). The muscle pathology revealed ragged-red and cytochrome c oxidase (COX) negative fibers in three patients. However, deficiencies in the activities of mitochondrial respiratory chain enzyme complexes were not detected in any of the patients’ muscle samples. Multiple deletions of mtDNA were detected in blood and muscle specimens but mtDNA depletion was not found. Due to these diagnostic difficulties, POLG-related syndromes are definitively diagnosed based on the presence of deleterious mutations in the POLG gene.